The Involvement of Endoplasmic Reticulum Stress in the SuppressionofColorectalTumorigenesisbyTolfenamicAcid

The nonsteroidal anti-inflammatory drug tolfenamic acid has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which tolfenamic acid exerts itsantitumorigenic effect remains unclear.Previous data from our group andothers indicate that tolfenamic acid alters expression of apoptosis- and cell-cycle arrest‐related genes in colorectal cancer cells. Here, we show that tolfenamic acid markedly reduced the number of polyps and tumor load in APC min/þ mice, accompanied with cyclin D1 downregulation in vitro and in vivo. Mechanistically, tolfenamic acid promotesendoplasmicreticulum(ER)stress,resultinginactivationoftheunfoldedproteinresponse(UPR) signaling pathway, of which PERK-mediated phosphorylation of eukaryotic translation initiation factor 2a (eIF2a)inducestherepressionofcyclinD1translation.Moreover,thePERK-eIF2a-ATF4branchoftheUPR pathway plays a role in tolfenamic acid-induced apoptosis in colorectal cancer cells, as silencing ATF4 attenuates tolfenamic acid-induced apoptosis. Taken together, these results suggest ER stress is involved in tolfenamic acid-induced inhibition of colorectal cancer cell growth, which could contribute to antitumorigenesis in a mouse model. Cancer Prev Res; 6(12); 1337–47. � 2013 AACR.